Caltech biologists reveal structure of protein responsible for weight loss in cancer and AIDS patients

PASADENA-Caltech biologists have determined the three-dimensional structure of a protein that causes wasting in cancer and AIDS patients. The discovery could lead to new strategies for controlling weight loss in patients with devastating illnesses-and conversely, perhaps new strategies for fighting obesity.

The protein is commonly known as ZAG and is found in most bodily fluids. But researchers have been aware for some time that the protein is particularly abundant in patients who have cancer.

More recently, researchers have discovered that the protein is involved in the wasting syndrome known as cachexia, which is associated with both cancer and AIDS.

"This protein has something to do with fat metabolism," says Pamela Bjorkman, a professor of biology at Caltech and associate investigator of the Howard Hughes Medical Institute. Bjorkman and her team recently published a paper in the journal Science showing ZAG's structure.

One of the most noteworthy features of the structure is the resemblance between ZAG and a family of proteins known as class I major histocompatibility complex molecules, or MHC.

"MHC proteins have a large groove that binds a peptide derived from a pathogen," says Bjorkman, explaining that their new picture of the ZAG crystal shows an unexpected blob in the ZAG counterpart of the MHC peptide binding grove.

"It's not a peptide, but some organic molecule," she says. "We suspect that it is involved in the function of ZAG. If this compound is involved in breaking down lipids, then maybe you could design a drug that replaces it and interfere with lipid breakdown."

According to Bjorkman, other research shows that tumor cells themselves seem to stimulate the body to overproduce ZAG somehow, which in turn leads to the breakdown of body fat.

Thus, people suffering from cachexia don't lose body weight because they don't eat, but because the fat in their bodies is ultimately destroyed by an interaction involving ZAG.

An intervention to stop the wasting, then, might be to disrupt the overexpression of ZAG, and this might be accomplished with monoclonal antibodies or small molecules that bind to ZAG, she says.

The research appeared in the March 19 issue of Science, and was also the subject of an article in HHMI news, published by the Howard Hughes Medical Institute.

The other authors of the paper are Luis Sanchez and Arthur Chirino, both senior research fellows in Bjorkman's lab.